1. Field of the Invention
The present invention relates to certain dihydropyrimidine, dihydropyrimidone and dihydropyrimidinethione compounds that can modulate the activity of calcium channels. These compounds can also be used for the treatment of diseases, such as cardiovascular disease, that are associated with calcium channels.
2. Description of the Related Art
The pharmacological function and importance of calcium antagonists or calcium channel blockers, has been well documented. See, for example, R. A. Janis and D. J. Triggle “New developments in Ca2+ channel antagonists” Journal of Medicinal Chemistry, 26, 775-785 (1983). Among the calcium antagonists, 4-aryl-1,4-dihydropyridine-3,5-dicarboxylic diesters (DUPs) of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases. For a review on Structure Activity Relations (SAR) see, S. Goldmann and J. Stoltefuss “1,4-Dihydropyridine: Effects of chirality and conformation on the calcium antagonist and calcium agonist activities” Angewandte Chemie International Edition (English) 30, 1559-1578 (1991). It was well documented that substitution on 4-phenyl ring is very crucial for pharmacological activity. Substituents at ortho or meta position improve the activity, whereas para substitution invariably decrease the activity. It was also published that bulkiness of ortho substituent, improves the calcium antagonist activity. B. Loev, M. M. Goodman, K. M. Snader, R. Tedeschi, E. Macko, “Hantzsch-Type Dihydropyridine hypotensive Agents”, Journal of Medicinal Chemistry 17, 956-965 (1974). Though dihydropyridines of nifedipine type have been used as anti-hypertensive agents, they have a serious disadvantage in treatment of hypertension. Since their plasma half-lives are relatively short, these drugs must be administered repeatedly to achieve enough clinical efficacy (Buhler, F. R.; Hukhten, U. L.; Kiowski, W. J. Cardiovasc. Pharamcol. 1982, 4, 350. Belz, G. G.; Spies, G. Excerpta Med. 1986, 177). This made researchers to look for more structural variations in the dihydropyridines ring. A number of compounds were known with variation in the dihydropyridine ring like dihydropyran (Bayer A. G. patent, DE 2235406.9, 1972), dihydrothiopyran (Bayer A. G. patent, DE 3212737.5, 1982), dihydropyridazine (Bayer A. G. patent, DE 834624, 1978), dihydropyrazine (Bayer A. G. patent, DE 3400765, 1984) and dihydropyrimidines (Baldwin et al, U.S. Pat. No. 4,675,321, 1987). Among these, dihydropyrimidines was the most potent class, which offered both potency and longer bioavailability.
Voltage-gated calcium channels are large trans-membrane proteins that regulate the intracellular concentration of calcium ions. They are classified into high (HVA) and low (LVA) voltage-activated channels, according to the membrane potential at which they are activated (E. Carbone and H. D. Lux. “A low voltage activated, fully inactivating Ca channel in vertebrate sensory neurons” Nature, 310, 501-502, 1984; B. Nilius, P. Hess, J. B. Lansman and R. W. Tsien “A novel type of cardiac calcium channel in ventricular cells.” Nature, 316, 443-446, 1985; M. C. Nowycky, A. P. Fox, R. W. Tsien. “Three types of neuronal calcium channels with different calcium agonist sensitivity” Nature 316, 440-443, 1985). LVA channels open and inactivate very fast, but deactivate about 10-100 times slower than HVA calcium channels. HVA channels require stronger membrane depolarizations to activate and can be divided further into N. P/Q,R and L-types based on their pharmacological properties. LVA channels can be detected in various tissues such as heart, brain, dorsal root ganglia and adrenal gland. The use of different search algorithms on mammalian expressed sequence tagged cDNAs or on similar sequences of the nematode Caenorhabditis elegans led to the identification of several genes, three of which encoded LVA calcium channels (T-type channels) and they have been named as α1G, α1H, α1I; (For Review, L. Lacinova, N. Klugbauer, F. Hofmann “Low voltage activated calcium channels: from genes to function” Gen. Physiol. Biophys, 19, 121-136, 2000. Of the above stated types of calcium channels, L-type channels received wide attention. Among the L-type channel blockers, Dihydropyridines (DHPs), dihydropyrimidines and dihydropyrimidinones are the most widely studied. But, most of the DHPs, dihydropyrimidines and dihydropyrimidinones are not selective against T-type channels and compounds inhibiting the T-type channels from these classes of compounds are still sparse.